United States Patent (19) 11) 4,339,589 Steglich et al. 45) Jul. 13, 1982

54 PREPARATION OF 4-SUBSTITUTED 52 U.S. C...... 548/228; 548/352; OXAZOLIDIN-5-ONES 562/441; 562/442; 562/443; 562/444; 562/445; (75) Inventors: Wolfgang Steglich, Berlin; Rudolf 562/446,562/553; 562/567; 562/568; 562/571; Hurnaus; Peter Gruber, both of 562/575; 562/433 Biberach; Boerries Kuebel, Berlin, all 58) Field of Search...... 548/228 of Fed. Rep. of Germany (56) References Cited 73) Assignee: BASF Aktiengesellschaft, Fed. Rep. U.S. PATENT DOCUMENTS of Germany 3,676,453 7/1972 Pines et al...... 548/228 (21) Appl. No.: 175,593 4,264,771 4/1981 Stealich et al...... 548/228 22 Filed: Aug. 5, 1980 Primary Examiner-David B. Springer Attorney, Agent, or Firm-Keil & Witherspoon Related U.S. Application Data 57 ABSTRACT 63 Continuation of Ser. No. 891,456, Mar. 29, 1978, Pat. Manufacture of 4-substituted oxazolinone-(5) com No. 4,264,771, which is a continuation of Ser. No. pounds, which are intermediates for substituted aminoa 484,068, Jul. 16, 1974, abandoned. cids, by alkylation of 2-substituted or 3,4-disubstituted (30) Foreign Application Priority Data oxazolinone-(5) compounds in an aprotic solvent in the Jul. 19, 1973 (DE) Fed. Rep. of Germany ...... 2336718 presence of a tertiary amine. 51) Int. Cl...... C07D 265/10 7 Claims, No Drawings 4,339,589 1. 2 zyl, diacetoxybenzyl, methylenedioxybenzyl and p PREPARATION OF 4-SUBSTITUTED chlorobenzyl. OXAZOLDIN-5-ONES Further possible substituents of the alkyl radicals are alkoxy, alkylthio, acylamino and carbethoxy radicals, This is a continuation of application Ser. No. 891,456, 5 such as methoxymethyl, S-methylthioethyl, y filed Mar. 29, 1978, now U.S. Pat. No. 4,264,771, which acetylaminopropyl, y-benzaminopropyl, 6 is a continuation of Ser. No. 484,068, filed July 16, 1974, acetylaminobutyl, 8-benzaminobutyl, carbethox now abandoned. ymethyl, carbethoxyethyl, 6-carbethoxymethyl and This invention relates to a process for the production g-carbethoxyethyl. , of 4-substituted oxazolinone-(5) compounds. 10 Examples of aryl R2 are phenyl, p-chlorophenyl, We have discovered a process for the manufacture of methoxyphenyl, dimethoxyphenyl, acetoxyphenyl and 4-substituted oxazolinone-(5) compounds, wherein 2 nitrophenyl. substituted oxazolinone-(5) compounds, which may Examples of cycloalkyl R2 are cyclopentyl, cyclo already have a substituent in the 4-position, are substi hexyl, cycloheptyl and cyclooctyl. tuted in the 4-position by reaction with an alkylating 15 The compounds of the formula I to be used as starting agent in an aprotic solvent in the presence of a tertiary materials can be obtained by conventional methods, for amine, and the resulting oxazolinone-(5) compound is example as described in the publication of H. E. Carter, optionally hydrolyzed to the aminoacid. "Organic Reactions'', Vol. III, page 198 (1949), or J. W. The starting materials are oxazolinone-(5) com Cornforth, "The Chemistry of Penicillin', edited by H. pounds of the general formula I 20 T. Clarke, J. R. Johnson and R. Robinson, Princeton University Press (1949), pages 730 et seq. H O I Alkylating agents are compounds by means of which alkyl or substituted alkyl radicals can be introduced into R?)-( compounds of the formula I. N - O 25 Examples of alkylating agents are therefore alkyl s halides, in particular alkyl bromides and alkyl iodides of Ri 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, and isobutyl bromides and iodides and 2-ethyl in which R1 is hydrogen, an unsubstituted or substituted hexyl bromide. The alkyl halides can contain double aromatic radical, straight-chain or branched-chain un 30 bonds and triple bonds. Allyl halides, such as allyl bro substituted or substituted alkyl of 1 to 20, preferably 1 to mide or prenyl chloride and propargyl halides, such as 10, carbon atoms, or a cycloaliphatic radical of 5 to 8 propargyl bromide or geranyl bromide, are preferred. ring members. In turn, the alkyl radicals can carry substituents and The preferred aromatic radical R1 is phenyl which accordingly the following can be used as alkylating can be substituted, for example by halogen, nitro, alk 35 agents: benzyl halides, for example benzyl chloride, oxy or lower alkyl, especially methyl or ethyl. benzyl bromide, nitrobenzyl chloride, dimethoxybenzyl Examples of substituted phenyl are chlorophenyl, chloride, p-chlorobenzyl bromide, methoxybenzyl bromophenyl, nitrophenyl, methoxyphenyl, dimethoxy chloride, 3,4-methylenedioxybenzyl chloride, acetoxy phenyl, tolyl and ethylphenyl. benzyl chloride, p-methylbenzyl chloride, 2,4-dimethyl Examples of suitable alkyl R1 are methyl, ethyl, pro benzyl chloride, 3,4-dimethylbenzyl chloride, trityl pyl, i-propyl-butyl, i-butyl, sec.-butyl, tert.-butyl, n-pen chloride or trityl fluoborate, halomethyl ketones, such. tyl, heptyl, octyl, decyl and dodecyl. as phenacyl bromide and chloroacetone, chloroacetic Examples of substituents of the alkyl radicals are acid or chloroacetic acid esters, for example ethyl chlo amino groups which carry an acyl radical as a substitu roacetate. ent of the nitrogen, such as 1-benzamino-isobutyl, 1 45 Tropylium perchlorate is a further example of a possi benzamino-2-phenyl-ethyl, benzaminomethyl, 1-ben ble alkylating agent. Zamino-ethyl and the corresponding acetamino radicals. As a rule, the reaction of a starting material with the Further substituents of the alkyl radicals are ester alkylating agent is carried out with equimolar amounts groups, nitrile and aryl radicals, especially phenyl radi in an anhydrous aprotic solvent in the presence of a cals, such as benzyl or 3-phenyl-ethyl. 50 tertiary amine as the base. However, one of the com Examples of cycloaliphatic radicals are cyclopentyl, pounds to be reacted can also be used in excess. cyclohexyl and cycloheptyl. Examples of suitable solvents to use are chlorinated The preferred starting compounds are 2-phenyl aliphatic hydrocarbons, such as methylene chloride or oxazolinone-(5) compounds which already have a sub chloroform, aromatic hydrocarbons, such as benzene or stituent in the 4-position, so that 4,4-disubstituted ox 55 toluene, amides of lower aliphatic carboxylic acids, in azolinone compounds are produced by the process of particular dimethylformamide or hexamethylphos the invention. phoric acid triamide, or dimethylsulfoxide, or mixtures R2 is hydrogen, straight-chain or branched-chain of the said solvents. alkyl of 1 to 20 carbon atoms, which can be substituted, . A solvent of low polarity, such as benzene, methy unsubstituted or substituted aryl or cycloalkyl of 5 to 8 lene chloride or tetrahydrofuran, is appropriate for very ring members. reactive alkylating agents, such as, for example, trityl Individual examples of R2 are: as alkyl-methyl, chloride, tropylium perchlorate or phenacyl chloride, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, pen for alkylation with alkyl halides, the use of dipolar tyl, heptyl, octyl, decyl, dodecyl and pentadecyl; as aprotic solvents, such as dimethylformamide, dimethyl substituted alkyl-in particular, alkyl substituted by 65 sulfoxide or hexamethylphosphoric acid triamide is phenyl which may be additionally substituted in the preferred. aromatic ring, such as benzyl, 9-phenylethyl, 3-phenyl Examples of suitable tertiary amines to use, which are propyl, methoxybenzyl, dimethoxybenzyl, acetoxyben in general employed in excess, are triethylamine, ethyl 4,339,589 3 4. diisopropylamine, so-called Hinig's bases (Hinig and Kiessel, Chem. Ber, 91, 308 (1958)), N,N-dimethyl CH3 CH-COCH3 cyclohexylamine, pyridine or picolines. Ethyldiiso N CH-C-COOH propylamine has proved a particularly suitable base. / In general, the reactions are carried out at tempera CH3 NH2 tures from 0° C. to room temperature or at elevated temperatures, suitably up to 100° C. At times it can also Further examples of aminoacids are a-phenacetyl glutamic acid, O-ethyl-lysine, a-propyl-ornithine and be appropriate to carry out the reaction at temperatures a-(o-nitrobenzyl)-ornithine. below 0°C., for example at -10° C. or below. 10 In some cases, for example when using benzyl chlo EXAMPLE 1 ride or ethyl chloroacetate as alkylating agents, the 4-allyl-2-phenyl-4-benzyl-oxazolinone-(5) addition of potassium iodide assists the alkylation. Working up the resulting 4-substituted oxazolinone 10 g (40 millinoles) of 2-phenyl-4-benzyl-oxazoli 15 none-(5) and 4.9 g (40 millimoles) of allyl bromide in 50 compounds presents no difficulties and is carried out by ml of absolute dimethylformamide are stirred with 6.75 conventional methods, for example by adding water g (51.5 millimoles) of ethyldiisopropylamine for 4 days and extracting by shaking with a water-insoluble or at room temperature. 200 ml of water are then added ganic solvent. and the mixture is extracted with five times 30 ml of It is surprising that under the reaction conditions 20 methylene chloride. The combined extracts are ex according to the invention the 4-substituted and 4,4- tracted by shaking with 0.5 N hydrochloric acid and disubstituted oxazolinone derivatives can be manufac with water and then dried over magnesium sulfate, and tured from optionally 2-substituted oxazolinone-(5) the solvent is evaporated off under reduced pressure. compounds without difficulties and in good to very 4-allyl-2-phenyl-4-benzyl-oxazolinone-(5) remains as a good yields, whilst from the known state of the art, for 25 yellow analytically pure oil, in a yield of 10.8 g (93%). example as with acylations, enolethers or mixtures with C19H17NO2 (291.4): Found C 78.27; H 6.18; N 4.98. the corresponding enolethers would have been ex Calculated C 78.36; H 5.88; N 4.81. pected. EXAMPLE 2 The following oxazolinone-(5) compounds may be 30 4-isopropyl-4-allyl-2-phenyl-oxazolinone-(5) mentioned in addition to the compounds indicated in 4 g of 4-isopropyl-2-phenyl-oxazolinone-(5) are the Examples: 4-(3-carbethoxyethyl)-4-cycloheptatrie stirred with 2.4 g of allyl bromide and 3.0 g of ethyl nyl-2-phenyl-oxazolinone-(5) (from I, R1 = C5H5, diisopropylamine in 20 ml of absolute dimethylformam R2=CH2CH2CO2C2H5 and tropylium perchlorate); ide at room temperature for 3 days. Amine hydrobro 4-(3-carbethoxyethyl)-4-phenacyl-2-phenyl-oxazoli 35 mide which precipitates is filtered off and the solution is none-(5) (from I, R1 = C6H5, R2=CH2CH2CO2C2H5 mixed with 150 ml of water and then extracted with five and phenacyl bromide); 4-ethyl-4-(6-acetaminobutyl)-2- times 30 ml of methylene chloride. The combined ex phenyl-oxazolinone-(5) from I, R1 = C6H5, tracts are extracted by shaking with 0.5 N hydrochloric acid and with water, and then dried over magnesium R2 = (CH2)4NHCOCH3 and ethyl iodide); 4-(3,3-dime 40 sulfate, and the solvent is distilled off under reduced thylallyl)-4-(y-benzaminopropyl)-2-phenyloxazolinone pressure. 4.8g of a yellowish liquid, representing 100% (5) (from I, R1 = C6H5, R2-(CH2)3NHCOCH3 and crude yield of 4-isopropyl-4-allyl-2-phenyl-oxazoli 3,3-dimethylallyl bromide); 4-propyl-4-(y-acetamino none-(5), remain. Distillation in a high vacuum gives 2.9 propyl)-2-phenyl-oxazolinone-(5) (from I, R1 = C6H5, g (60%) of an almost colorless liquid of boiling point 98 R2 = (CH2)3NHCOCH3 and propyl iodide). 45 C. at 0.1 mm Hg. The substituted oxazolinones prepared in accordance C15H17NO2 (243.3): Found C 74.12; H 7.08; N 5.76. with the invention are excellent starting materials for Calculated C 74.09; H 7.03; N 5.75. the manufacture of aminoacids, preferably of a-sub EXAMPLE 3 stituted amino-acids. For example, al-alkyl derivatives of the aminoacids glycine, alanine and leucine and the 50 4-isopropyl-4-benzyl-2-phenyl-oxazolinone-(5) corresponding noraminoacids, phenylalanine, protected 4.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5), 3.0 g of derivatives of tyrosine, dopa, lysine, ornithine, arginine, ethyldiisopropylamine and 2.53 g of benzyl chloride are histidine, tryptophan and half-esters of aspartic and stirred in 20 ml of absolute dimethylformamide, with a glutamic acid can be manufactured. 55 little added potassium iodide, for 4 days at room tem perature. The mixture is then diluted with 150 ml of For this purpose, the oxazolinones can be used as water and extracted with five times 30 ml of methylene pure substances or in the form resulting from the alkyla chloride. The combined extracts are shaken with 0.5 N tion according to the invention, without undergoing hydrochloric acid and with water, and then dried with purification. magnesium sulfate, and the solvent is distilled off under The hydrolysis to the aminoacid is as a rule carried 60 reduced pressure. 4-isopropyl-2-phenyl-4-benzyl out under said conditions, by conventional methods. oxazolinone-(5) remains as a pale yellow oil which is For this purpose, a mixture of glacial acetic acid and approx. 85% pure. Distillation gives 2.3 g (40%) yield. concentrated aqueous hydrochloric acid is used with EXAMPLE 4 advantage. 65 It is of interest that the hydrolysis of 4-(propin-(2)-yl)- 4-isopropyl-2-phenyl-4-(2-nitrobenzyl)-oxazolinone-(5) 2-phenyl-4-isopropyl-oxazolinone-(5) gives the levu 4.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5), 3.0 g of linic acid derivative of the formula ethyldiisopropylamine and 3.42 g of 2-nitrobenzyl chlo 4,339,589 5 6 ride in 20 ml of absolute dimethylformamide are stirred chloride is slowly added dropwise, whilst stirring. After for 3 days at room temperature. The mixture is then stirring for 2 days, the violet solution is extracted by diluted with 150 ml of water and extracted with five shaking with 40 ml of 0.5N hydrochloric acid and dried times 30 ml of methylene chloride. The combined ex with magnesium sulfate, and the solvent is distilled off tracts are extracted by shaking with 0.5N hydrochloric under reduced pressure. The solid which remains is acid and with water, and then dried with magnesium digested with ethyl acetate, filtered off and washed with sulfate, and the solvent is distilled off under reduced ethyl acetate. This leaves 2.2 g (27%) of 2-phenyl-4-tri pressure. The solid residue is recrystallized from ethyl phenylmethyl-oxazolinone-(5) as a colorless powder of acetate/petroleum ether. 6.6 g (66%) of 4-isopropyl-2- melting point 183° C.; after recrystallization from ben phenyl-4-(2-nitrobenzyl)-oxazolinone-(5) are obtained 10 zene/ethyl acetate, the melting point is 192 C. (with as colorless crystals; the melting point is from 113 to decomposition). 116° C., and 121 C. after a further recrystallization. C28H21NO2 (403.5): Found C 83.37; H 5.14; N 3.30. C19H16N2O4 (338.4): Found C 67.26; H 5.57; N 8.28. Calculated C 83.35; H 5.24; N 3.47. Calculated C 67.45; H 5.36; N 8.28. (b) 13.0 g of trityl fluoborate are dissolved in 80 ml of EXAMPLE 5 15 methylene chloride, 6 ml of absolute a-picoline are added whilst cooling in a mixture of ice and common 4-isopropyl-2-phenyl-4-(2-oxo-phenylethyl)-oxazoli salt, and a solution of 4.8g of 2-phenyl-oxazolinone-(5) none-(5) r in 60 ml of methylene chioride is then very slowly 11.8g of 4-isopropyl-2-phenyl-oxazolinone-(5) and 12 added dropwise at -10 C., whilst stirring. After 2 g of phenacyl bromide are dissolved in 20 ml of ethyl days, the mixture is extracted by shaking with 0.5 N diisopropylamine and 5 ml of dimethylsulfoxide. The hydrochloric acid and then dried with magnesium sul solution is then heated to 70° C. for 2.5 hours, in the fate, and the methylene chloride is removed whilst course of which a thick white precipitate forms. The replacing it, in portions, by ethyl acetate. The precipi mixture is evaporated under reduced pressure, the resi tate formed is then filtered off and washed with ethyl due is taken up in methylene chloride and the solution is 25 acetate. 6.1 g (50%) of melting point 182 C. remain. washed with 0.1 N hydrochloric acid and water, dried and again evaporated. The solid which remains is re EXAMPLE 9 crystallized from chloroform/hexane. : 2-phenyl-4,4-bis-cycloheptatrienyl-oxazolinone-(5) Yield: 12.5g (67%) of 4-isopropyl-2-phenyl-4-(2-oxo phenylethyl)-oxazolinone-(5) of melting point 151C. 30 5 g of 2-phenyl-oxazolinone-(5), 5 g of tropylium (from tetrahydrofuran). perchlorate and 10 ml of triethylamine in 80 ml of ben C20H19NO3 (321.4): Found C 75.07; H 6.03; N 4.42. zene are stirred for 3 hours at room temperature. Ethyl acetate is added to the violet solution which is succes Calculated C 74.75; H 5.96; N 4.36. sively extracted by shaking with dilute hydrochloric EXAMPLE 6 35 acid and sodium bicarbonate solution, dried over so 4-isopropyl-2-phenyl-4-cycloheptatrienyl-oxazolinone dium sulfate and evaporated. The oily residue is crystal (5) lized from methanol. 2-phenyl-4,4-bis-cycloheptatrie 4-isopropyl-2-phenyl-oxazolinone-(5) in methylene nyl-oxazolinone-(5) crystallizes in yellow needles of chloride is reacted with an equimolar amount of melting point 109 to 111° C. The yield is 3.45 g (33%). tropylium perchlorate and triethylamine for 12 hours at 40 C23H19NO2 (341.4): Found C 80.35; H 5.72; N 3.99. O' C. The mixture is then extracted by shaking with 0.1 Calculated C 80.91; H 5.61; N 4.10. N hydrochloric acid and dried with magnesium sulfate, EXAMPLE 10 and the solvent is distilled off under reduced pressure. This leaves 4-isopropyl-4-cycloheptatrienyl-2-phenyl 4-methyl-2-phenyl-4-benzyl-oxazolinone-(5) oxazolinone-(5) as a spectroscopically pure pale yellow 45 2.5g of 2-phenyl-4-benzyl-oxazolinone-(5) and 2.4g oil, in over 90% yield. of methyl iodide in 10 ml of absolute dimethylformam ide are stirred with 2.4 g of ethyldiisopropylamine for 5 EXAMPLE 7 hours at 90° C. The mixture is then diluted with 100 ml 4-isopropyl-2-(1'-benzamino)-isobutyl-4-cyclohepta of water and extracted with five times 20 ml of methy trienyloxazolinone-(5) 50 lene chloride. The combined extracts are extracted by The oxazolinone obtained from N-benzoyl-DL-Val shaking with 0.5 N hydrochloric acid and with water Val-OH by heating with a five-fold excess of acetic and then dried with magnesium sulfate, and the solvent anhydride to 110° C. for 15 minutes is reacted, in methy is evaporated off under reduced pressure. Distillation of lene chloride, with equimolar amounts of triethylamine the residue in a high vacuum gives a colorless oil of and tropylium perchlorate for 12 hours at 0° C. The 55 boiling point 113 to 115° C. at 0.07 mm Hg, in a yield mixture is then extracted by shaking with 0.1 N hydro of 0.9 g (34%). chloric acid and dried over magnesium sulfate, and the C17H5NO2 (265.3): Found C 76.64; H 5.85; N5.30. solvent is distilled off under reduced pressure. This Calculated C 77.00; H 5.70; N 5.28. leaves 4-isopropyl-2-1'-benzanino)-isobutyl-4- cycloheptatrienyl-oxazolinone-(5) as a spectroscopi 60 EXAMPLE 11 cally pure, pale yellow oil in more than 90% yield. 4-(4-isopropyl-2-phenyl-oxazolinon-(5)-yl)-acetic acid ethyl ester EXAMPLE 8 4.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5), 4.9 g of. 2-phenyl-4-triphenylmethyl-oxazolinone-(5) 65 ethyl chloroacetate, 6.0 g of ethyldiisopropylamine and (a) 6.0 g of trityl chloride and 3.0 ml of a-picoline are 1.0 g of potassium iodide in 20 ml of absolute dimethyl dissolved in 30 ml of methylene chloride. A solution of formamide are stirred for 6 hours at 95 C. The mixture 3.2 g of 2-phenyl-oxazolinone-(5) in 30 ml of methylene is then diluted with 20 ml of water and extracted with 4,339,589 7 8 five times 30 ml of methylene chloride. The combined as a colorless liquid, boiling point from 107 to 111° C. extracts are washed with 0.5 N hydrochloric acid and at 0.2 mm Hg. with water and then dried with magnesium sulfate, and the solvent is evaporated off under reduced pressure. EXAMPLE 1.5 Distillation of the residue in a high vacuum gives a 4-(propin-(2)-yl)-2-phenyl-4-benzyl-oxazolinone-(5) yellow oil of boiling point 130° C. at 0.15 mm Hg, in a yield of 4.35 g (75%). F 2.5 g of 2-phenyl-4-benzyl-oxazolinone-(5), 2.4 g of C16H19NO4 (289.3): Found C 66.20; H 6.62; N 5.05. propargyl bromide and 3.0 g of ethyldiisopropylamine Calculated C 66.43; H 6.62; N 4.84. in 10 ml of absolute dimethylformamide are stirred O either (a) for 4 hours at 95° C. or (b) for 3 days at room EXAMPLE 12 temperature. (a) 4-(2-phenyl-4-benzyl-oxazolinon-(5)-yl)-acetic acid In both cases, the reaction solution is evaporated ethyl ester under reduced pressure, the residue is dissolved in 30 ml 2.5 g of 2-phenyl-4-benzyl-oxazolinone-(5), 2.45 g of 15 of methylene chloride and the solution is washed with ethyl chloroacetate, 3.6 g of ethyldiisopropylamine and 100 ml of 0.5 N hydrochloric acid, 100 ml of sodium 0.5 of potassium iodide in 10 ml of absolute dimethyl bicarbonate solution and 100 ml of water. It is then formamide are stirred for 6 hours at 95 C. The mixture dried with magnesium sulfate and the solvent is evapo is then diluted with 100 ml of water and extracted with rated off under reduced pressure. The oils which remain five times 20 ml of methylene chloride. The combined 20 crystallize gradually. Recrystallization from ether/pe extracts are washed with 0.5 N hydrochloric acid and troleum ether in each case gives 1.25 g (43%) of yellow with water and then dried with magnesium sulfate, and ish crystals of melting point 64° C.; after distillation in a the solvent is evaporated off under reduced pressure. 2.9 g of a brown oil, which slowly crystallizes in the high vacuum (boiling point 160° C. at 0.1 mm Hg), the refrigerator, remain. Recrystallization from ether/pe 25 product is analytically pure and almost colorless, and troleum ether gives 1.50 g (45%) of colorless crystals of melts at 64 C. melting point 80 C. C19H15NO2 (289.2): Found C 78.51; H 5.29; N 5.06. C20H19NO4 (337.4): Found C 71.13; H 5.84; N 4.23. Calculated C 78.90; H 5.22; N 4.84. Calculated C 71.20; H 5.68; N 4.15. EXAMPLE 16 (b) 0.5g of 4-(2-phenyl-oxazolinon-(5)-yl)-acetic acid 30 ethyl ester, 0.26 g of benzyl chloride, 0.3 g of ethyldiiso 4-isopropyl-4-(propin-2-yl)-2-phenyl-oxazolinone-(5) propylamine and 0.1 g of potassium iodide in 5 ml of 2.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5), 2.4 g of absolute dimethylformamide are stirred for 4 days at propargyl bromide and 3.0 g of ethyldiisopropylamine room temperature. Working up carried out as in Exam 35 in 10 ml of dimethylformamide are stirred for 3.5 days at ple 12(a) gives 0.6 g of a yellow oil which matches the room temperature. The mixture is then evaporated product obtained under 12(a). under reduced pressure, the residue is taken up in 50 ml EXAMPLE 13 of ethyl acetate, the solution is washed once with 100 ml 4-ethyl-4-benzyl-2-phenyl-oxazolinone-(5) of 0.5N hydrochloric acid, once with 100 ml of sodium 40 2.5 g of 4-benzyl-2-phenyl-oxazolinone-(5), 3.0 g of bicarbonate solution and once with 100 ml of water and ethyl iodide and 3.0 g of ethyldiisopropylamine in 10 ml then dried with magnesium sulfate, and the solvent is of absolute dimethylformamide are stirred for 9 hours at evaporated off under reduced pressure. Distillation, in a 95 C. The mixture is then diluted with 100 ml of water high vacuum, of the oil which remains gives a colorless and extracted with five times 20 ml of methylene chlo 45 liquid, of boiling point from 103 to 104 C. at 0.25 mm ride. The combined extracts are washed with 0.5 N Hg, in a yield of 1.75 g (72.5%). hydrochloric acid and with water, dried with magne C15H15NO2 (241.3): Found C 74.54; H 6.39;N 5.81. sium sulfate, and freed from the solvent under reduced Calculated C 74.66; H 6.26; N 5.81. pressure. Distillation in a high vacuum gives 0.9 g (32%) of 4-ethyl-4-benzyl-2-phenyl-oxazolinone-(5) as a 50 EXAMPLE 17 pale yellow oil of boiling point 127° C. (0.04 mm Hg). 4-geranyl-4-isopropyl-2-phenyl-2-oxazolinone-(5) The compound is pure, according to the NMR spec 2.0 g of 4-isopropyl-2-phenyl-2-oxazolinone-(5) in 10 trum. ml of absolute dimethylformamide are mixed with 1.5g EXAMPLE 4 55 of ethyldiisopropylamine. 2.17 g of geranyl bromide, 2-benzyl-4-isopropyl-4-(propen-2-yl)-2-oxazolinone-(5) dissolved in 10 ml of absolute dimethylformamide, are added dropwise in the course of 7 hours at room tem 2.6 g of 2-benzyl-4-isopropyl-2-oxazolinone-(5), 3.0 g perature, whilst stirring. After stirring for 3 days at of allyl bromide and 4.5g of ethyldiisopropylamine in room temperature, the mixture is worked up by pouring 15 ml of absolute dimethylformamide are stirred for 3 60 days at room temperature. The mixture is then diluted it into 200 ml of 0.5N hydrochloric acid and extracting with 100 ml of water and extracted five times with 20 ml with four times 30 ml of ether. The combined extracts of methylene chloride. The combined extracts are are extracted by shaking with 150 ml of water, dried washed with 0.5 N, hydrochloric acid and with water and freed from the solvent under reduced pressure. The and then dried with magnesium sulfate, and the solvent 65 analytically pure compound is left as a pale yellow oil, is removed under reduced pressure. On distillation in a in a yield of 3.1 g (91%). high vacuum, the red-yellow oil gives 2.0 g (65%) of C22H29NO2 (339.5) Calculated C 77.84 H 8.61 N 4.13. 2-benzyl-4-isopropyl-4-(propen-2-yl)-2-oxazolinone-(5) Found C 77.77 H 8.67 N 4.21. 4,339,589 9 O 5 ml of concentrated hydrochloric acid are added and Hydrolysis of 4-substituted oxazolinones-(5) to the mixture is stirred for 6 hours at 95 C. It is then o-aminoacids evaporated under reduced pressure, the residue is dis 1. a-benzyl-valine from solved in a mixture of ethyl acetate and water (ratio 4-isopropyl-2-phenyl-4-benzyl-oxazolinone-(5) 1:1), and the aqueous phase is separated off, concen 2.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5), 1.9 g of trated to approx. 10 ml and neutralized to pH 7 with benzyl chloride, 2.5g of ethyldiisopropylamine and 0.5 sodium bicarbonate. This produces a colorless precipi g of potassium iodide in 10 ml of absolute dimethyl tate which is filtered off and washed with water, ace formamide are stirred for 4 days at room temperature. tone and ether. The yield is 2.2g, representing 44% The dimethylformamide is then distilled off under re 10 based on 4-isopropyl-2-phenyl-oxazolinone-(5); the duced pressure, the residue is taken up in 30 ml of meth product is a colorless powder which sublimes from ylene chloride, the solution is washed with 100 ml of 0.5 approx. 270° C. onward. N hydrochloric acid and 100 ml of water and then dried C12H16N2O4 (252.2): Found C 56.73; H 6.25; N 10.91. with magnesium sulfate and the solvent is evaporated Calculated C 57.15; H 6.39;N 11.11. off under reduced pressure. This leaves 2.8g of a pale 15 yellow liquid which according to the NMR spectrum 4. a-methyl-phenylalanine from consists of : 85% of 4-isopropyl-2-phenyl-4-benzyl 4-methyl-2-phenyl-4-benzyl-oxazolinone-(5) oxazolinone-(5) and 15% of benzyl chloride. 2.5 g of 2-phenyl-4-benzyl-oxazolinone-(5) and 2.8 g. This liquid is dissolved in 15 ml of glacial acetic acid of methyl iodide in 10 ml of absolute dimethylformam and 10 ml of concentrated aqueous hydrochloric acid 20 ide are stirred with 3.0 g of ethyl diisopropylamine for and the solution is stirred for 7 hours at 95 C. The solvent is then evaporated off under reduced pressure 5 hours at 90° C. The mixture is then diluted with 100 ml and the residue is taken up in a mixture of chloroform of water and extracted with 5 times 20 ml of methylene and water (in the ratio of 1:1). The aqueous phase is chloride. The combined extracts are extracted by shak separated off, concentrated and neutralized with n 25 ing with 100 ml of 0.5 N hydrochloric acid and with 100 butylamine to a pH value of 7. It is then evaporated to ml of water and then dried with magnesium sulfate, and dryness and the solid which remains is shaken with the solvent is distilled off under reduced pressure. This methanol, filtered off and rinsed with a little methanol. leaves 2.6 g of a yellow oil which according to the The yield of a-benzyl-valine is 0.73 g, representing NMR spectrum contains 75% of 4-methyl-2-phenyl-4- 35% based on 4-isopropyl-2-phenyl-oxazolinone-(5) 30 benzyl-oxazolinone-(5). employed. The product is a colorless powder which This oil is dissolved in 20 ml of glacial acetic acid, 10 sublimes from 240° C. onward. ml of concentrated hydrochloric acid are added and the C12H17NO2 (207.3) Mass spectrum (high resolution): mixture is stirred for 5 hours at 95°C. It is then evapo 208. 135; C12H18NO2=M-1 rated, the residue is taken up in 50 ml of water and 50 ml 35 of ethyle acetate, and the aqueous phase is separated off 2. a-(2-nitrobenzyl)-valine from and again evaporated. The substance left is dissolved in 4-isopropyl-2-phenyl-4-(2-nitrobenzyl)-oxazolinone-(5) a little water and charged onto a column containing 50 1.7 g of 4-isopropyl-2-phenyl-4-(2-nitrobenzyl)- ml of Lewatit MP 62 ion exchanger (OH form), which oxazolinone-(5) in 15 ml of glacial acetic acid and 15 ml is then eluted with 200 ml of water. The eluate is evapo of concentrated hydrochloric acid are stirred for 6 40 rated in vacuo, leaving a colorless powder, weighing hours at 95 C. The mixture is then evaporated under 0.9 g, which represents 50% yield based on 2-phenyl-4- reduced pressure, the residue is taken up in 30 ml of benzyl-oxazolinone-(5); this product sublimes from ap water and the solution is extracted by shaking with pox. 230° C. onward. tetrachloromethane. The aqueous phase is separated off CoH3NO2 (179.2): Found C 66.45; H 7.30; N 7.78. and concentrated to approx. 10 ml under reduced pres 45 Calculated c 67.03; H 7.31;N 7.81. sure. It is then neutralized to pH 7 with sodium hydrox ide and ultimately with sodium bicarbonate. A colorless 5. a-benzyl-aspartic acid from precipitate results, which is filtered off and recrystal 4-(2-phenyl-4-benzyl-oxazolinon-(5)-yl)-acetic acid lized from methanol. Yield: 0.9 g, corresponding to ethyl ester 72%; melting point 262 C. (with decomposition). 50 2.5g of 2-phenyl-4-benzyl-oxazolinone-(5), 2.45 g of C12H16N2O4 (252.3): Found C 56.97; H 6.62; N 11.12. ethyl chloroacetate, 3.0 g of ethyldiisopropylamine and Calculated C 57.16; H 6.39;N 11.11. 0.5g of potassium iodide in 10 ml of absolute dimethyl formamide are stirred for 6 hours at 95 C. The dimeth 3. a-(p-nitrobenzyl)-valine from ylformamide is then distilled off under reduced pressure 4-isopropyl-2-phenyl-oxazolinone-(5) 55 and the residue is dissolved in methylene chloride, ex 4.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5) and 3.4 tracted by shaking with water and again evaporated. g of p-nitrobenzyl chloride in 20 ml of absolute dimeth The brown oil which remains is stirred with 25 ml of ylformamide are stirred with 3.0 g of ethyldiisopropyla glacial acetic acid and 5 ml of concentrated hydrochlo mine and 0.3 g of potassium iodide for 3 days at room ric acid for 8 hours at 90° C. The solution is evaporated temperature. The mixture is then diluted with 200 ml of 60 in vacuo, the residue is dissolved in a little water/me water and extracted with five times 30 ml of methylene thanol and this solution is neutralized with n-butylamine chloride, and the combined organic phase is extracted and buffed to pH 4 with glacial acetic acid. The mixture by shaking with 0.5 N hydrochloric acid and with wa is again evaporated and the residue is taken up in ace ter, then dried with magnesium sulfate and evaporated tone. On standing overnight, a colorless precipitate under reduced pressure. This leaves 6.0 g of a brown oil 65 forms, and this is filtered off, giving 0.67 g, correspond which according to the NMR spectrum contains 82% ing to 30% yield, based on 2-phenyl-4-benzyl-oxazoli of 4-isopropyl-2-phenyl-4-p-nitrobenzyl)-oxazolinone none-(5). This product is a white powder which decom (5). This oil is dissolved in 30 ml of glacial acetic acid, poses above 275 C. 4,339,589 11 C11H3NO4 (223.2): Found C 59.37; H 6.11; N 6.36. Calculated C 59.20; H 5.86; N 6.27. 6. a-isopropyl-3,4-dimethoxyphenylalanine from 4-isopropyl-2-phenyloxazolinone-(5) 2.0 g of 4-isopropyl-2-phenyl-oxazolinone-(5), 1.86 g of 3,4-dimethoxybenzyl chloride, 1.5 g of ethyldiiso propylamine and 0.5g of potassium iodide in 10 ml of wherein absolute dimethylformamide are stirred for 7 days at 10 R1 is phenyl which may be unsubstituted or substi room temperature. The mixture is then diluted with 100 tuted by chlorine, bromine, nitro, methoxy, di ml of water and extracted with five times 20 ml of meth methoxy, methyl or ethyl, and ylene chloride. The combined extracts are washed with R2 is hydrogen, methyl or benzyl which is substituted 0.5 Nhydrochloric acid and with water, then dried with by one or more hydroxy, alkoxy, acetoxy, trifluo magnesium sulfate and freed from the solvent under 15 romethyl, halogen or methyl, and reduced pressure. This leaves 3.45g of a light yellow oil R3 is an alkyl of 1 to 4 carbons, -CH2OH, -CH (OH)CH3, -CH2SH, -CH2CH2SCH3, -CH which according to the NMR spectrum contains 2CO2H, -CH2CH2CO2H, -CH2-(CH2)2-NH2, approx. 65% of the desired product. -CH2-(CH2)3-NH2, -CH2CH2C This oil is dissolved in 20 ml of glacial acetic acid and 20 10 ml of concentrated aqueous hydrochloric acid and H(OH)CH2NH2, the solution is stirred for 6 hours at 95 C. It is then evaporated under reduced pressure and the residue is NH taken up in a mixture of 50 ml of ethyl acetate and 50 ml of water. The aqueous phase is separated off and con 25 -CH2-(CH2)2-NH-C-NH2, -at-(O) centrated to approx. 10 ml. It is then neutralized with n-butylamine and the aminoacid is precipitated by add OH ing methanol/ether and filtered off. The yield of a-isopropyl-3,4-dimethoxyphenylala nine is 0.4g, representing 15% based on 4-isopropyl-2- 30 phenyl-oxazolinone-(5) employed. The product is a -a-(O)- OH, --O). OH, colorless powder which melts at 260° C. OCH3 7. a-methyl-3,4-dimethoxyphenylalanine from 4-methyl-2-phenyl-oxazolinone-(5) 35 1.75 g of 4-methyl-2-phenyl-2-oxazolinone-(5), 1.86g -(C) OCH3, -CH2 of 3,4-dimethoxybenzyl chloride, 1.5 g of ethyldiiso propylamine and 0.3 g of potassium iodide in 10 ml of absolute dimethylformamide are stirred for 4 days at room temperature. The mixture is then diluted with 100 ml of water and extracted with five times 20 ml of meth ylene chloride. The combined extracts are washed with 0.5 N hydrochloric acid and with water, dried with 45 magnesium sulfate and freed from the solvent under which consists essentially of reacting an oxazoli reduced pressure. According to the NMR spectrum, the none-(5) compound of the formula resulting light yellow oil 3.1 g) contains approx. 50% of the desired product. The oil is dissolved in 10 ml of O glacial acetic acid, 10 ml of concentrated aqueous hy 50 H drochloric acid are added and the mixture is stirred for 7 hours at 95 C. After evaporation under reduced pres sure, the residue is taken up in 50 ml of water and 50 ml of carbon tetrachloride, leaving a substantial amount of 55 insoluble resin to be separated off. The water phase is wherein evaporated in vacuo, the residue is dissolved in metha R1 and R2 are defined above, with a compound of the nol and the solution is charged onto a column of 50 ml formula R3X where R3 is defined above and X is of Levatit (R) MP 62 (OH form). After elution with 100 bromine, chlorine or iodine in an anhydrous 60 aprotic solvent in the presence of a tertiary amine ml of methanol, the eluate is concentrated and the prod selected from the group consisting of triethylam uct is precipitated with ether. Yield 0.35 g, representing ine, ethyldiisopropylamine, a Hunig's base, N,N- 15% based on 4-methyl-2-phenyl-oxazolinone-(5) em dimethyl-cyclohexylamine, pyridine and a picoline ployed. The product is a white powder which decom at temperatures of from about -10° C. to 100 C., poses at about 230 C. 65 whereby the oxazolinone-(5) compound is substi We claim: tuted in the 4-position, with the proviso that when 1. A process for the manufacture of a 4-substituted R2 is substituted benzyl, then R3 can only be an oxazolinone-(5) compound of the formula alkyl of 1 to 4 carbons; when R2 is hydrogen and 4,339,589 13 14 R is an alkyl of 1 to 4 carbons, then of said alkyl R3 can only be -CH3, -CH(CH3)2, -CH(CH3)CH2CH3 or -CH2CH(CH3)2, other -CH2 wise R3 can be any of the above shown substitu ents; and, when R2 is methyl, then R3 can only be and X is chlorine or iodine. OH OCH3 5. The process of claim 1 wherein R2 is hydrogen, R3 is -CH2CO2H and X is chlorine. 10 6. The process of claim 1 wherein R2 is methyl, R3 is -CH2 OH or -CH2 OCH3.

OCH3 2. The process of claim 1 wherein said aprotic solvent 15 is dimethylformamide, dimethylsulfoxide, hexamethyl phosphoric acid triamide, methylene chloride, benzene -CH2 (O) OCH3 or tetrahydrofuran. 3. The process of claim 1 wherein said tertiary amine 20 and X is chlorine. is ethyldiisopropylamine. 7. The process of claim 1 wherein R2 is 3,4-dime 4. The process of claim 1 wherein R2 is hydrogen, R3 thoxybenzyl or 3,4-dihydroxybenzyl and R3 is methyl. k ck k . . S

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